Cystic fibrosis (CF) is an autosomal recessive genetic desease that affects all systems with epithelial surfaces, including the lungs, pancreas, glands that secrete mucus in the intestines, liver and sweat glands. It has a high mortality and morbidity, and develops as a result of the mutation of CF transmembrane conductance regulator (
Term and preterm newborn babies hospitalized due to respiratory distress in the Neonatal Intensive Care Unit at Manisa Celal Bayar University Hospital, Manisa, Turkey, between May 2017 and January 2018, were included in this study. The control group consisted of term and preterm infants who had no respiratory distress. The study was approved by the Manisa Celal Bayar University Medical School Ethics Review Board. Infants with congenital anatomic respiratory disease, congenital heart disease, perinatal asphyxia, meconium aspiration syndrome, and respiratory distress due to metabolic and hematological causes, were not included in the study. Infants with respiratory distress due to cesarean section (C-section) were also excluded from the study.
DNA isolation from blood samples obtained from each infant was performed at the Medical Genetics Laboratory, Ege University Medical Faculty, Izmir, Turkey. DNA amplification was performed using thermal cycler (GeneAmp PCR System 9600; Applied Biosystems, Foster City, CA, USA). A Sanger sequence [capillary electrophoresis (CE)] platform was used for sequence analysis. All exons of the
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 18.0 for Windows program (
Forty babies, 20 with respiratory distress and 20 babies without respiratory distress, were included in the study. Demographic characteristics of the infants revealed that the mean gestational age was 36.22 ± 3.89 weeks. Twenty-one of the infants were born preterm and 19 were born at term. Twenty-two were girls and 18 were boys. The mean birth weight was 2775.5 ± 952.9 g, the mean birth height was 47.07 ± 5.45 cm and the mean head circumference was 33.02 ± 3.2 cm. Demographic characteristics of the babies in the control and patients groups are shown in Table 1. In the patient group, the mean gestational age was 34.25 ± 4.65 weeks; 14 infants were born preterm and six were born at term. In the control group, the mean gestational age was 38.2 ± 1.15 weeks; seven of them were born preterm and 13 were born at term. The prenatal histories taken from the patient and control groups revealed that the maternal age was similar in both groups. No significant difference was found between the patient and the control groups with regard to incidence of placental abruption, placenta previa, chorioamnionitis, gestational diabetes, diabetes mellitus, preeclampsia and eclampsia, and prenatal steroid administration.
Demographic characteristics of the control group and the patient group.
Gender: | |||
females | 11 | 11 | 1.000 |
males | 9 | 9 | |
Mean birth weight (g) ± SD (min-max) | 3278.00 ± 585.62 (1970.00–4180.00) | 2273.00 ± 94.63 (610.00–3850.00) | 0.297 |
Mean birth height (cm) ± SD (min-max) | 49.95 ± 1.80 (45.00–53.00) | 44.20 ± 6.37 (33.00–51.00 | 0.186 |
Mean head circumference (cm) ± SD (min-max) | 34.55 ± 1.15 (31.50–37.00) | 31.50 ± 3.84 (23.00–37.00) | 0.134 |
Delivery type: | |||
NspD | 5 | 0 | 0.017 |
C-section | 15 | 20 | |
Gestational age (weeks) | 38.20 ± 1.16 (37.00–41.00) | 35.25 ± 4.65 (26.00–40.00) | 0.062 |
Intrauterine growth retardation ( |
2 | 4 | 0.091 |
Median Apgar score (1st min.) (min-max) | 8 (7–9) | 7 (5–8) | 0.009 |
Median Apgar score (5th min.) (min-max) | 9 (9–10) | 8 (7–9) | 0.001 |
The pathologies and treatments of infants admitted to the neonatal intensive care unit in the patient group are listed in Table 2. The mean duration of stay on mechanical ventilation in the patient group was 2.25 ± 4.49 days, and the mean duration of oxygen therapy was 13.35 ± 20.71 days. The mean length of hospital stay in the patient group was 24.65 ± 21.32 days. Of the 20 infants in the control group, 14 were admitted to the neonatal intensive care unit due to hyperbilirubinemia, one for urinary tract infection, four for hypernatremic dehydration, and one for intrauterine growth restriction. The mean length of hospital stay in the control group was 4.75 ± 1.97 days.
Pathologies and treatments of infants in the patient group.
Respiratory distress syndrome (RDS) ( |
9 |
Congenital pneumonia ( |
2 |
Pneumonia ( |
4 |
Transient tacypnea of newborn ( |
5 |
Surfactant treatment ( |
5 |
Mechanical ventilation treatment ( |
11 |
Mean duration of mechanical ventilation (days) | 2.25 ± 4.49 (1.00–20.00) |
nCPAP treatment ( |
13 |
Mean duration of nCPAP (days) | 9.10 ± 15.43 (1.00–51.00) |
Oxygen treatment ( |
17 |
Mean duration of oxygen therapy (days) | 13.35 ± 20.71 (1.00–66.00) |
Bronchopulmonary dysplasia (BPD) ( |
3 |
Steroid treatment ( |
|
IV | 0 |
inhaled | 5 |
Patent ductus arteriosus ( |
4 |
Pulmonary hypertension ( |
1 |
Sepsis ( |
|
clinical | 18 |
proven | 2 |
Intraventricular hemorrhage ( |
1 |
Mean length of stay in hospital (days) | 24.65 ± 21.32 (9.00–71.00) |
When the clinical symptoms and signs of respiratory distress in 20 infants in the patient group were taken into account, four had a cough, five were wheezing, 10 were grunting, three had apnea, 19 had tachypnea, 15 had retraction, and 12 had findings in lung auscultation (rales/rhonchi) (Table 3). When the laboratory findings of 20 infants in the patient group were examined, five of them had a positive C-reactive protein (CRP). The mean CRP value was 0.59 ± 1.14 mg/dl. Ten of the infants had leuko-cytosis with a mean leukocyte value of 11651 ± 5109.40 mm3. Two of the infants had thrombocytopenia, the average platelet count was 258.45 ± 11.6402.42 mm3. Five infants had metabolic acidosis. The mean values of the parameters were as follows: pH 7.31 ± 0.11, bicarbonate (HCO3) 21.44 ± 3.34 mmol/L, base deficit −3.36 ± 4.42, partial pressure of carbon dioxide (PCO2) 47.61 ± 13.16 mmHg and partial pressure of oxygen (pO2) 57.39 ± 40.56 mmHg. With regard to the radiological findings of 20 infants in the patient group, 14 had lung infiltration and six had a ground-glass appearance compatible with respiratory distress syndrome (RDS).
Symptoms and signs of respiratory distress in the patient group.
Cough | 4 |
Wheezing | 5 |
Grunting | 10 |
Apnea | 3 |
Tachpnea | 19 |
Retraction | 15 |
Rales/rhonchi | 12 |
Prolonged expiration | 1 |
Tachycardia | 2 |
Oxygen requirement | 17 |
Hypotonia | 6 |
In the control group,
Normal ( |
14 |
E1228G (C.3683A>G) het. ( |
1 |
E217G (c.3683A>G) het. ( |
1 |
E632TfsX9) (c.1894_1895delAG) het. ( |
1 |
1807M (c.2421A>G) het. ( |
2 |
S573F (c.1718C>T) het. ( |
1 |
Normal ( |
16 |
A46D (c.137C>A) het. ( |
1 |
D1312G (c.3935A>G) het. ( |
1 |
R117H (c.350G>A) het. ( |
1 |
S1426P (c.4276T>C) het. ( |
1 |
The symptoms and diagnoses of infants that heterozygous
E1228G (c.3683A>G) heterozygous | asymptomatic | hyperbilirubinemia |
E217G (c.650A>G) heterozygous | asymptomatic | hyperbilirubinemia |
E632TfsX9 (c.1894_1895delAG) het. | asymptomatic | hyperbilirubinemia |
1807M (c.2421A>G) heterozygous | asymptomatic | hyperbilirubinemia |
1807M (c.2421A>G) heterozygous | asymptomatic | hyperbilirubinemia |
S573F (c.1718C>T) heterozygous | symptomatic | hypernatremic dyhydration |
A46D (c.137C>A) heterozygous | tachypnea; oxygen requirement | respiratory distress syndrome (RDS) |
D1312G (c.3935A>G) heterozygous | tachypnea; retraction | respiratory distress syndrome (RDS) |
R117H (c.350G>A) heterozygous | tachypnea; retraction | transient tachypnea of newborn |
S1426P (c.4276T>C) heterozygous | cough; wheezing | pneumonia |
Cystic fibrosis is a multi-system disease affecting lungs, gastrointestinal system, sweat glands and reproductive system. It may lead to progressive respiratory failure months, even years after birth [6]. Cystic fibrosis is caused by mutations on a single large gene on chromosome 7, which encodes the CFTR protein. Clinical disease requires disease-causing mutations on both copies of the
Mutations of the CFTR gene have been divided into five different classes. Class I mutations: defective protein production, class II mutations: defective protein processing, class III mutations: defective regulation, class IV mutations: defective conduction, class V mutations: reduced amounts of functional
Clinical disease generally requires pathogenic mutations on both copies of the
A c.1718C>T heterozygous mutation was detected in an infant without respiratory distress. The c1718C>T heterozygous mutation is phenotypically reported to result in an elevated immunoreactive trypsinogen (IRT) in the neonatal period (
In two infants who had no respiratory distress in the control group, a c.2421A>G heterozygous mutation was detected. This has been evaluated as a polymorphism found in the French population [17]. In the Cystic Fibrosis Mutation Database, the c.2421A>G heterozygous mutation has been reported in eight patients (
A c.3683A>G heterozygous mutation was also found in an infant who had no respiratory distress. This mutation was reported in a 9-year-old Turkish girl by Kilinc
Another infant in the control group had a heterozygous mutation c.650A>G. In the Cystic Fibrosis Mutation Database, this mutation was detected in a 2-year-old Portuguese male patient who had a sweat chloride concentration of 60.0–80.0 mEq/L and had pancreatic insufficiency and moderate lung disease [18]. This type of mutation was also detected in one patient by Yoshimura
A heterozygous mutation, c.1894_1895delAG, was detected in one infant in the control group. There was no reported case of this mutation in the literature review of the
A c.137C>A heterozygous mutation was detected in an infant who had respiratory distress. This mutation has so far been detected in patients with severe respiratory symptoms and high chloride levels in the sweat test. This mutation was found in two Greek patients with CF. One of these patients was 18 years old, his sweat chloride level was 80.0 mEq/L, respiratory function tests revealed FEV1 58.0% and he had pseudomonas infections; the other patient was 30 years old with a sweat chloride level of 92.5 mEq/L, respiratory function tests revealed FEV1 92.5%, and he had pseudomonas infections and pancreatic insufficiency [20].
A c.3935A>G heterozygous mutation was detected in an infant in the patient group. In the Cystic Fibrosis Mutation Database, this mutation was detected in a 14-year-old male patient in 2008. He had a negative sweat test and chronic sinusitis, pseudomonas-infected bronchitis, short stature and growth retardation were reported in this patient (
A c.4276T>C heterozygous mutation was found in an infant in the patient group. In the Cystic Fibrosis Mutation Database, this mutation was reported in a patient with congenital bilateral absence of vas deferens in 1999 (
A c.350G>C heterozygous mutation was found in an infant in the patient group. This mutation is one of the 10 common mutations seen in CF (F508del, I507del, V520F, G551D, G542X, R553X, R117H, 621+1G>T, N1303K, A455E). The disease phenotype of this mutation can range from asymptomatic to classic CF disease. Therefore, genetic counseling is also challenging because of the phenotypic changes associated with this mutation [21].
In this study, no significant difference was found in the
This study demonstrates the importance of